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The Scap-SREBP1-S1P/S2P lipogenesis signal orchestrates the homeostasis and spatiotemporal activation of NF-κB

Fei, Xia, Huang, Jiaqi, Li, Fei, Wang, Yuejue, Shao, Zhehua, Dong, Lingling, Wu, Yinfang, Li, Boran, Zhang, Xue, Lv, Baihui, Zhao, Yun, Weng, Qingyu, Chen, Kaijun, Zhang, Min, Yang, Shiyi, Zhang, Chao, Zhang, Min, Li, Wen, Ying, Songmin, Sun, Qiming, Chen, Zhihua, Shen, Huahao·2023·Cell Reports
DOI 10.1016/j.celrep.2023.112586
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Abstract

The nuclear factor κB (NF-κB) pathway plays essential roles in innate and adaptive immunity, but little is known how NF-κB signaling is compartmentalized and spatiotemporally activated in the cytoplasm. Here, we show that the lipogenesis signal cascade Scap-SREBP1-S1P/S2P orchestrates the homeostasis and spatiotemporal activation of NF-κB. SREBP cleavage-activating protein (Scap) and sterol regulatory element-binding protein 1 (SREBP1) form a super complex with inhibitors of NF-κB α (IκBα) to associate NF-κB close to the endoplasmic reticulum (ER). Upon lipopolysaccharide (LPS) stimulation, Scap transports the complex to the Golgi apparatus, where SREBP1 is cleaved by site-1 protease (S1P)/S2P, liberating IκBα for IκB kinase (Ikk)-mediated phosphorylation and subsequent activation of NF-κB. Loss of Scap or inhibition of S1P or S2P diminishes, while SREBP1 deficiency augments, LPS-induced NF-κB activation and subsequent inflammatory responses. Our results reveal the Scap-SREBP1 complex as an additional cytoplasmic checkpoint for NF-κB homeostasis and unveil the Golgi apparatus as the optimal cellular platform for NF-κB activation, providing insights into the crosstalk between lipogenesis signaling and immunity.

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Metadata

Authors
Fei, X., Huang, J., Li, F., Wang, Y., Shao, Z., Dong, L., Wu, Y., Li, B., Zhang, X., Lv, B., Zhao, Y., Weng, Q., Chen, K., Zhang, M., Yang, S., Zhang, C., Zhang, M., Li, W., Ying, S., Sun, Q., Chen, Z., & Shen, H.
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-06
Volume
42
Issue
6
Pages
112586
ISSN
2211-1247
DOI
10.1016/j.celrep.2023.112586
Cited by
42
References
4
Language
en
Licence
Funders
  • Natural Science Foundation of Zhejiang Province (LD21H010001)
  • Zhejiang University
  • National Natural Science Foundation of China (31970826, 81930003, 82090012)

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